Alzheimer's disease is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visuospatial skills, and behavior deficits. Characteristics of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain, and other regions of the brain, neurofibrillary tangles, and accumulation of the amyloid B peptide (AB).
In Alzheimer's, two main proteins form abnormal polymers (aggregates) in the brain that are believed to result from misfolding during aggregation of one of twenty nonhomologous human proteins. The intracellular neurofibrillary tangles-NFT's are made from the microtubule-associated protein (tau protein) and the extracellular “amyloid” plaques consist mainly of polymerized AB-peptide. Both are toxic to the brain neurons and are the result of fibers formed from the subunit protein by stacking of beta strands. See B. Bulic, E. Mandelkow et al. Angewandte Chemie International Edition, Vol. 48, Issue 10, pgs. 1740-1752, 2009 and B. Bulic, et al. J. Med. Chem 2013 Jun. 13; 56(11):4135-55. See also US2014275040, CN103450152, US2009203903, US2009233945, WO2012106343, US20150031672, WO2010129816, WO2008103615, and US20080027044.
Tubulin-associated unit, or Tau, is a microtubule-associated protein that is thought to play a critical role in the etiology of Alzheimer's disease (AD) based on several lines of evidence. First, intracellular aggregates of hyperphosphorylated tau (NFTs) are invariably found in the brains of patients with AD and several other neurodegenerative diseases. Second, the extent of NFT pathology in the brain of AD patients is closely correlated with cognitive function. Finally, while mutations in tau have not been shown to cause AD, such mutations do cause another form of dementia known as frontotemporal dementia with parkinsonism (FTDP). Therefore, approaches aimed at reducing NFTs and/or hyperphosphorylated tau represent disease modifying treatments for AD.
Currently histological analysis of autopsy materials is the primary means of detecting tau aggregates. A tau PET tracer would be a valuable non-invasive tool for spatial and temporal quantification of neurofibrillary tangles (NFTs) in human brain, since post-mortem studies have shown NFT burden to better correlate with cognitive decline. A tau PET tracer will be a critical disease-relevant tool for quantifying a stabilization or decrease of NFT formation for disease-modifying Alzheimer's disease therapeutics. Additionally, a tau PET tracer could be useful for patient selection for AD clinical trials. In this mode, a tau PET tracer could be developed as a companion diagnostic. In addition to AD, there are other neurodegenerative diseases characterized by the deposition of tau aggregates (frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease, etc.).
Therefore, a need exists for neuroimaging radiotracers that would allow in vivo imaging of tau pathology thereby providing insight into the deposition of tau aggregates in the human brain. The successful neuroimaging radiotracer must cross the blood-brain barrier and posses high affinity and specificity for tau aggregates and therefore must have appropriate lipophilicity (log D 1-3) and low molecular weight (, <450), show rapid clearance from blood and low non-specific binding. The neuroimaging radiotracer will play a role in diagnosis by identifying patients with excess tau aggregates in the brain and therefore at risk for developing AD as well as shed light on the degree of tau aggregation, effect on the brain over time, the correlation with cognition and aid in the analysis of the efficacy of a tau inhibitor.
In a typical PET study, a small amount of radiotracer is administered to the experimental animal, normal human or patient being tested. The radiotracer then circulates in the blood of the subject and may be absorbed in certain tissues. The radiotracer may be preferentially retained in some of these tissues because of specific enzymatic conversion or by specific binding to macromolecular structures such as proteins. Using sophisticated imaging instrumentation to detect positron emission, the amount of radiotracer is then non-invasively assessed in the various tissues in the body. The resulting data are analyzed to provide quantitative spatial information of the in vivo biological process for which the tracer was designed. PET gives pharmaceutical research investigators the capability to assess biochemical changes or metabolic effects of a drug candidate in vivo for extended periods of time, and PET can be used to measure drug distribution, thus allowing the evaluation of the pharmacokinetics and pharmacodynamics of a particular drug candidate under study. Importantly, PET tracers can be designed and used to quantitate the presence of binding sites in tissues. Consequently, interest in PET tracers for drug development has been expanding based on the development of isotopically labeled biochemicals and appropriate detection devices to detect the radioactivity by external imaging.
While the primary use of the isotopically labeled compounds of this invention is in positron emission tomography, which is an in vivo analysis technique, certain of the isotopically labeled compounds can be used for methods other than PET analyses. In particular, 14C and 3H labeled compounds can be used in in vitro and in vivo methods for the determination of binding, receptor occupancy and metabolic studies including covalent labeling. In particular, various isotopically labeled compounds find utility in magnetic resonance imaging, autoradiography and other similar analytical tools.